The overall objective of this proposal is to elucidate the mechanism by which caspase-8 promotes T cell activation. Immune responses are characterized by massive expansion of lymphocytes to eliminate foreign antigens, followed by massive apoptosis to achieve homeostasis. It remains unclear how the apoptotic machinery is kept intact in proliferating lymphocytes to ensure their ultimate demise. Caspase-8 is an initiator caspase critical for lymphocyte apoptosis. However, recent studies indicate that paradoxically, caspase-8 is also required for lymphocyte proliferation. Caspase-8 is made in latent form (procaspase-8), and during apoptosis it undergoes two processing events to generate mature caspase-8. We have found that this activation is triggered by procaspase-8 oligomerization and involves the generation of processing intermediates that are proteolytically competent but enzymatically different from the fully processed mature caspase-8. During lymphocyte activation, procaspase-8 becomes associated with a complex formed by Bcl10 and MALT1, both being critical mediators of antigenic signaling. We will 1) establish the mechanism that controls procaspase-8 activation during lymphocyte proliferation, 2) determine the form of procaspase-8 that promotes lymphocyte proliferation, and 3) identify and characterize the substrates of the proliferative form of caspase-8. The embedment of an apoptotic protein into the cell proliferative pathway effectively links the control of lymphocyte life and death. The proposed study will thus shed important light on the interplay between these two fundamental cellular processes in immunity, and will have practical implications for caspase-based therapy for hyperproliferation and deficiency of the immune system.